1. Field of Invention
The present invention relates to a novel process for the preparation of 2-alkoxy-N-(1-azabicyclo[2.2.2]octan-3-yl) aminobenzamides which have gastrokinetic and antiemetic pharmacologic properties. The process utilizes an N,N'-dialkylcarbodiimide condensation agent such as N,N'-dicyclohexylcarbodiimide (DCC) to react a strong mineral acid salt of 3-aminoquinuclidine or a loweralkyl substituted 3-aminoquinuclidine with an aminobenzoic acid derivative to form a benzamide in a medium comprised of 50 to 90 volume % pyridine and 50 to 10 volume % water wherein the equivalent ratio of strong acid to 3-aminoquinuclidinyl radical is 1:1 during reaction. The products of the invention always have a 2-methoxy radical and an amino radical on the benzene ring and may have other radicals on the benzene ring and are variously referred to herein as above or as quinuclidinyl subst-aminobenzamides.
2. Information Disclosure Statement
Preparation of amides from a carboxylic acid and an amine utilizing an N,N'-dialkylcarbodiimide as condensation agent in certain organic solvents is a known general procedure. However, the use of pyridine and water is not a general practice. Moreover, the benzoic acids of the present invention are also substituted by an amino group which must remain intact during the reaction and must not enter into the condensation reaction. The high solubility of 2-alkoxy-aminobenzoic acids in pyridine was not previously known.
The condensation reaction between the carboxylic acid group of an adenine derivative made functional by the amine group of a macromolecule also of adenine derivation utilizes a carbodiimide, including DCC, in water or in a mixture formed by water and water soluble organic solvent (e.g., pyridine, tetrahydrofuran, dioxane, etc.) at temperatures of 5.degree. to 50.degree. C., preferably at room temperature, has been disclosed in U.S. Pat. No. 4,088,639. In that disclosure the amount of pyridine exemplified in relation to water is less than and out of the range of the present invention and the reactants are of a macromolecular nature.
Preparation of N-(1-azabicyclo[2.2.2]octan-3-yl) benzamides substituted by an amino radical on the benzamide moiety in yields of 15-38% is disclosed in French Pat. No. 2,529,548. In that patent a yield of 15% of 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide maleate from reaction of 4-amino-5-chloro-2-methoxybenzoic acid, 3-aminoquinuclidine dihydrochloride and ethyl chloroformate in dimethylformamide and triethylamine followed by preparation of the salt was reported. The method of preparation disclosed does not employ an N,N'-dialkylcarbodiimide. In contrast, the present invention employs a monoprotonated strong acid salt of a 3-aminoquinuclidine in pyridine water solution.
In an application U.S. Ser. No. 597,275, filed on Apr. 6, 1984, 2-alkoxy-N-(1-azabicyclo[2.2.2]octan-3-yl) aminobenzamides were disclosed from reaction of such as 4-amino-5-chloro-2-methoxybenzoic acid and 3-aminoquinuclidine in tetrahydrofuran utilizing 1,1-carbonyldiimidazole as condensation agent. The method requires the free base of a 3-aminoquinuclidine which is difficult to obtain and the condensation agent is toxic and thus the method is impractical for large scale production.